Certain complex amides of lysergic acid (I, R.dbd.OH, also named as 9-ergolene-8.beta.-carboxylic acid) are found in ergoted rye; i.e., rye contaminated by the growth of the filamentous fungus Claviceps purpurea. Persons eating bread prepared from ergoted rye were subject to ergot poisoning, known in the Middle Ages as St. Anthony's Fire because of the feeling of intense heat in the extremities. Ergot poisoning was often fatal. The peripheral vasoconstrictor properties of the ergot alkaloids, as a group, is responsible for the fatalities seen with ergot poisoning, with gangrene of the extremeties being a common precipitating factor. ##STR1## Two dozen ergot alkaloids have been characterized from isolates from Claviceps purpurea infestations. Derivatives of lysergic acid include the simple amides, ergine (R.dbd.NH.sub.2) and ergonovine (ergometrine) ##STR2## and the pepetide alkaloids (R=a complex amide derived from a cyclized polypeptide) including ergotamine, ergosine, ergocornine, ergocryptine, ergocristine, etc. The corresponding alkaloids based on isolygergic acid (9-ergolene-8.alpha.-carboxylic acid) are also present and are named by changing the "ine" ending to "inine"; e.g. ergotaminine, ergosinine, etc.
The ergot alkaloids as a group have several interesting pharmacologic activities; uterine contraction (oxytocic action), peripheral vasoconstriction, adrenergic blockade, and serotonin antagonism as well as varied CNS activities including the production of hallucinations. Certain of the alkaloids individually are used to produce post-partum uterine contractions and in the treatment of migraine. Pharmacologic activity, toxicity and central effects vary from alkaloid to alkaloid. In general, hydrogenation of the delta-9 double bond results in compounds of lowered activity as regards peripheral action but adrenolytic and central inhibition of vasomotor centers is enhanced.
Derivatives of lysergic acid and dihydrolysergic acid are too numerous to mention, but include, generically, substitution on the indole nitrogen, and at C-2 (.alpha.-bromocryptine is a 2-bromo derivative), replacement of the carboxamide function at C-8 by various groups, particularly cyanomethyl, methylthiomethyl, methoxymethyl as well as substitution of simpler amide groups (butanolamide.dbd.methysergide) for the complex "polypeptide chains" or simple hydroxy amides of the natural alkaloids.
There has been considerable speculation, frequently followed by a synthetic effort, as to what portions of the ergoline molecule are responsible for activity; i.e., are part-structures possible which retain, perhaps selectively, the pharmacologic activity of the parent alkaloid? One part-structure which has been examined is the aminotetrahydronaphthalene structure II from which the B and D rings of an ergoline have been subtracted. ##STR3## where R is carboxamide, hydroxy, amino etc. The elements of a .beta.-phenethylamine can also be discerned from I using the phenyl ring and carbons 5 and 10 plus the nitrogen at 6, a part structures in which only the A ring is retained. In addition, tricyclics lacking the B (indole) ring as well as benz[c]indoles (lacking the D ring--see U.S. Pat. No. 4,110,339) have been prepared. None of these part-structures seemed to have the desired degree of activity as regards the dopamine D-2 agonist activity (prolactin inhibition etc) of ergocornine, dihydroergocornine, lergotrile or pergolide (U.S. Pat. Nos. 3,920,664, 4,054,660 and 4,166,182, for example). However, recently Kornfeld and Bach have found that the A ring of an ergoline is not required for D-2 agonist activity. These new part structures are named as hexahydropyrrolo[4,3-g]quinolines--see U.S. Pat. No. 4,235,909. A related structure, a hexahydropyrazolo[4,3-g]quinoline, U.S. Pat. No. 4,198,415, also had excellent D-2 agonist action. The corresponding 2-ring compounds, in which the D ring of the ergoline is opened to leave a dialkylamine substituent on the C ring, are also active D-2 agonists--see U.S. Pat. Nos. 4,235,226 for the amino-substituted isoindoles, and 4,276,300 for the amino-substituted indazoles (analogous to the three-ring pyrazoles). It has now been found that other hetero ring systems than pyrrole and pyrazole can be attached to the perhydroquinoline ring (rings B+C of an ergoline). One of these is a pyrimidine--see Nichols and Kornfeld, U.S. Pat. No. 4,501,890.
2-Amino-6-dialkylaminotetrahydroquinazolines, (a two-ring benzopyrimidine) are not known.